Chlamydia trachomatis is an obligate intracellular bacteria that infects the mucosal epithelium of the female genital tract. Mice injected intravaginally with a host-adapted strain of C. Trachomatis designated mouse pneumonitis (MoPn) develop an ascending infection of the uterus which is cleared by the host immune response within three to four weeks. To determine the nature of this adaptive immunity, shown previously to involve the induction of protective CD4+ T cells, attempts were made to polarize the host immune system towards either a Th1 or Th2 phenotype by, in vivo administration of monoclonal antibodies reactive with Th1- versus Th2-associated cytokines. Bacterial clearance in mice treated with antibodies specific for the Th2 cytokine, IL-4, occurred at a rate similar to that of untreated controls while clearance in animals receiving antibodies reactive with the Th1-inducing cytokine, IL-12, was significantly delayed, indicating a primary role for Th1 cells in murine resistance to C. Trachomatis infection. This was confirmed in mice carrying a germline deletion for the Th1-derived cytokine, interferon-gamma, where low level genital tract infections persisted for up to 90 days post-infection. Finally, the role of T cells bearing the conventional alpha/beta antigen receptor molecule versus the mucosally-targeted gamma/delta receptor molecule was compared using mice carrying germline deletions for either the beta or delta chain of the respective receptor. Results indicated that elimination of gamma/delta receptor-positive T cells had no effect on bacterial clearance whereas the absence of alpha/beta receptor-positive T cells was associated with constant high level shedding of organisms. In summary, these data implicate CD4+ Th1 cells bearing an alpha/beta+ T cell receptor molecule as the primary mediators of protection against mucosal Chlamydia infections.